By capitalizing on the initially puzzling observations of unpredictable transgene silencing and variable expression, plant scientists have pioneered research into a novel type of epigenetic regulation, termed homology-dependent gene silencing. This silencing process has implications for natural mechanisms of gene expression in plants and other eukaryotes, and has branched out into studies of reversible DNA modifications; RNA metabolism, transport and processing; and host responses to plant viruses, viroids and transposable elements. The analysis of transgene silencing systems has enriched our understanding of other epigenetic phenomena, including paramutation, as well as heterosis and genome evolution. This research is also highly relevant to the biotechnology industry, which is interested in avoiding unwanted transgene silencing in genetically engineered lines and in exploiting various types of silencing to inactivate specific genes. Homology-dependent gene silencing can also be used in high-throughput approaches for functional genomics.